Postpartum breast cancer, defined as the diagnosis of breast cancer within 5 years of pregnancy, has a 3-fold increased risk for distant recurrence and mortality. A postpartum diagnosis is an independent risk factor for poor prognosis, isolating the postpartum window from potential tumor promotional attributes of pregnancy. The postpartum mammary gland undergoes involution to return the lactation-competent gland to a non-secretory state. In rodent models, postpartum involution is tumor-promotional due to tissue remodeling and macrophage infiltration. Unknown is whether the postpartum period also exhibits stromal remodeling at secondary sites, which could increase metastasis. The question of whether normal physiologic tissue remodeling occurs in organs besides the mammary gland in the postpartum period, and escalates breast cancer metastasis, has not been previously explored. My novel observation that macrophages infiltrate the postpartum liver, reminiscent of mammary gland involution, suggests that postpartum liver tissue remodeling establishes a pro-metastatic microenvironment during weaning-induced involution. The hypothesis that macrophage infiltration in the postpartum liver establishes a pro-metastatic microenvironment that supports breast cancer metastasis; and further, that prophylactic treatment with NSAIDs reduces the pro-metastatic attributes of the regressing liver as well as liver metastases, will be tested. Aim 1 will determine the extent of macrophage infiltration into the liver during involution including a characterization of the pro-tumor immunosuppressive differences of macrophages in the postpartum liver compared to nulliparous controls. The contribution of infiltrating macrophages to liver involution and the postpartum pro-metastatic microenvironment will be evaluated using a conditional macrophage-depletion mouse model. Aim 2a will test if mammary tumor cell metastasis is increased in the postpartum period using murine models of metastatic postpartum breast cancer. Aim 2b will test if liver metastasis is increased in University of Colorado postpartum breast cancer patients when compared to their nulliparous breast cancer peers. Aim 3 will determine if treatment with NSAIDs in our murine model of postpartum breast cancer decreases the pro-metastatic attributes of the postpartum liver and reduces liver metastasis. This work will further contribute to our understanding of the postpartum period as a window of risk for metastatic breast cancer by investigating the role of the liver pro-metastatic microenvironment. The proposal aims to identify novel treatment options for young women at risk for postpartum breast cancer. The project's progression will be frequently assessed by the Schedin lab research team and collaborators with complimentary expertise in basic science and clinical fields. To accomplish these aims, proficiency in flow cytometric, histologic, & macrophage functional assays, use of transgenic, metastasis, and treatment murine models, as well as human clinical databases will advance the student's scientific breadth to better understand human postpartum breast cancer.